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Oncotarget. 2015 Sep 22;6(28):24990-5002. doi: 10.18632/oncotarget.4572.

Characterization of tumor infiltrating lymphocytes in paired primary and metastatic renal cell carcinoma specimens.

Author information

1
Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.
2
Department of Dermatology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
3
Department of Biology, School of Health and Natural Sciences, University of Saint Joseph, West Hartford, CT, USA.
4
Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
5
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.

Abstract

Renal cell carcinoma (RCC) is one of the most chemo- and radio-resistant malignancies, with poor associated patient survival if the disease metastasizes. With recent advances in immunotherapy, particularly with PD-1/PD-L1 blockade, outcomes are improving, but a substantial subset of patients does not respond to the new agents. Identifying such patients and improving the therapeutic ratio has been a challenge, although much effort has been made to study PD-1/PD-L1 status in pre-treatment tumor. However, tumor infiltrating lymphocyte (TIL) content might also be predictive of response, and our goal was to characterize TIL content and PD-L1 expression in RCC tumors from various anatomic sites. Utilizing a quantitative immunofluorescence technique, TIL subsets were examined in matched primary and metastatic specimens. In metastatic specimens, we found an association between low CD8+ to Foxp3+ T-cell ratios and high levels of PD-L1. High PD-L1-expressing metastases were also found to be associated with tumors that were high in both CD4+ and Foxp3+ T-cell content. Taken together these results provide the basis for combining agents that target the PD-1/PD-L1 pathway with agonist of immune activation, particularly in treating RCC metastases with unfavorable tumor characteristics and microenvironment. In addition, CD8+ TIL density and CD8:Foxp3 T-cell ratio were higher in primary than metastatic specimens, supporting the need to assess distant sites for predictive biomarkers when treating disseminated disease.

KEYWORDS:

metastatic; primary; renal cell carcinoma (RCC); tumor infiltrating lymphocytes (TILs)

PMID:
26317902
PMCID:
PMC4694809
DOI:
10.18632/oncotarget.4572
[Indexed for MEDLINE]
Free PMC Article

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